6beta:19-oxido-pregnenes



United States Patent 3,346,569 65:19-0XIDO-PREGNENES' Albert Wettstein,Rieheu, Georg Anner, Karl Heusler, and Jaroslav Kalvoda, Basel, HellrnutUeberwasser, Rieheu, and Jules Heer, Binningen, Switzerland, assignorsto Ciba Corporation, New York, N.Y., a corporation of Delaware NoDrawing. Filed Sept. 7, 1962, Ser. No. 222,202

Claims priority, application Switzerland, June 2, 1961, 6,779/61; Sept.18, 1961, 10,803/61; Sept. 22, 1961, 11,071/61; Jan. 9, 1962, 85/62 9Claims. (Cl. 260-23955) This application is a continuation-in-part ofour copending application Ser. No. 122,657, filed July 10, 1961, byAlbert Wettstein et al., and now abandoned.

The present invention relates to novel A -3-oxo-6flzl9- oxido-pregnenes,more especially to compounds of the formula wherein R stands forhydrogen, oxo or hydrogen together with hydroxy or acyloxy, R stands forhydrogen, hydroxy, acyloxy or 160tI17a-epOXi'Cle groupings, R stands for0x0 or hydrogen together with hydroxy or acyloxy.

The acyloxy radicals mentioned above, representing esterified hydroxylgroups, are more especially those of aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, arahphatic, aromatic or heterocycliccarboxylic acids containing at most 15 carbon atoms, such as for exampleformic, acetic, propionic, butyric, valeric, tri'methylacetic, caproic,oenantic, decanoic, trifluoroacetic, carbonic-monomethylor ethyl ester,hexahydrobenzoic, cyclopentyl-propionic, pheny1-propionic Ibenzoic orfuroic acids.

The compounds of the present invention are extremely usefulintermediates for the production of 19-norpregnanes to which class ofcompounds belong several well known progestational agents such as19-nor-progesterones, 17u-hydroxy-l9-nor-progesterone and especially itsesters, 6-dehydro-19-nor-progesterone. However some of the compounds ofthe invention are also useful in themselves such as the6B:19-OXidO-1l-oxo progesterone or can be used for the production ofuseful 19-oxygenated progesterones such as 19oxo-progesterone. The 6,8:l9-oxido-11- 0110- and the 19-0xo-derivatives of progesterone arecapable for protecting against bacterial endotoxins even Whenadministered at very low dosages.

The l9-nor-pregnenes are produced from the A -3-oxo-6/3219-oxido-pregnenes of the present invention by reduction with zincin acetic acid at slightly elevated temperature and by elimination ofthe angular C-19-substituent in the A -3-oxo-l9-hydroxy-pregnenesobtained in known manner, preferably after oxidizing the 19-hydroxygroup to an aldehyde or acid function.

Among the A -3-oxo-6fl:19-oxido-pregnenes of the invention the followingare particularly important: A -3 20- dioxo-6B: l9-oxido-pregnene, A -3:20-dioxo-6fi: 19; 16041 17 aabisoxido-pregnene, A -3 :20-dioxo-6fl: 19oxido 170chydroxy-pregnene and its esters, more especially its acetate,propionate, caproate etc. A -3:20-dioxo-6,8:19-oxidollu-hydroxy-pregneneand its esters, A -3:11:20-trioxo- 6,8: 19-.oxido-pregnene.

The pregnenes of the invention are obtained e.g. by treating a3-oxigenated rx-halogen-6fi-hy-droxy-pregnane 3,346,569 Patented Oct.10, 1967 With lead tetraacetate in boiling benzene or cyclohexane forseveral hours to form the corresponding 3-oxygenated Sa-halogen-GB:l9-oxido-steroid. These compounds may alternatively be prepared byreacting a 3-oxigenated 5ozhalogen-6fl-hydroxy pregnane in boilingcyclohexane solution with monovalent positive iodine in the presence offree iodine and strong visible light for 10 to minutes. The monovalentpositive iodine may be obtained from N-iodosuccinimide or from silveracetate and iodine or mercuric acetate and iodine. An especiallyefiicient method for the production of the 5a-halogen-6/9:l9-oxido-pregnanes consists in treating a5ot-halogen-6B-hydroxy-pregnane in an apolar solvent e.g. boilingcyclohexane solution with lead tetraacetate and iodine. The 3-oxigenated5a-halogen-6fi: l9-oxido-pregnanes obtained are then transformed intothe A 3-oxo-pregnenes of the invention (if desired after introduction ofother functional groups, e.g. a 17a-hydroxy group by theenolacetate-peracid method) by alkaline hydrolysis of a 3-acyloxy grouppresent and oxidation of the 3-hydroxy group to a 3-oxo-group by meansof chromium trioxide. Under the influence of a base such as pyridine orsodium acetate hydrohalic acid is easily eliminated from the3-0xo-Sa-halogen-6B:19-oxido-pregnanes to form A -3- oxo-6/i':19-oxido-pregnenes.

The following examples illustrate the invention. The temperatures aregiven in centigrades.

Example 1 A suspension of 10 grams of calcium carbonate and 30 grams oflead tetraacetate in 1 liter of cyclohexane is heated to 80 C., treatedwith 8.0 grams of iodine and then with 5 grams of3p:20,8-diacetoxy-5a-chloro-fi-hydroxy-5a-pregnane and the reactionmixture is refluxed for 3 hours and then cooled and filtered. Theresidue is washed with ether, the filtrate exracted With sodiumthiosulfate solution of 10% strength, dried and evaporated under reducedpressure, to yield 6.1 grams of a solid crude product which oncrystallization from acetone-I- hexane yields pure3,8:ZOfl-diacetoxy-Sa-chloro-6/3:l9- oxido-5a-pregnane melting at 148 to150 C. Optical rotation [a] =+25 (in chloroform).

A solution of 4.0 grams of this compound in methanol is treated with 4.0grams of potassium carbonate and water and refluxed for one hour, thenevaporated in a Water-jet vacuum and from the residue the crude3flz20l3- dihydroxy-5a-chloro-6/8:l9-oxido-5a-pregnane melting at 237 to240 C. is isolated in the usual manner.

A mixture of 1.0 gram of the above compound, 50 cc. of pyridine and 2.2grams of chromium trioxide is stirred for 20 hours at 60 C. and thereaction mixture is then worked up as usual. Recrystallization of thecrystalline residue yields pure A -3:20-dioxo-6fl:l9-oxido-pregnene(6,6:19-0xido-progesterone) melting at 142143 C. Optical rotation [cc]=-18.8 (in chloroform).

Example 2 (a) A suspension of grams of lead tetraacetate and 5 0 gramsof dry calcium carbonate in 4.5 liters of cyclohexane is stirred forabout 40 minutes at the boil. 25 grams of3/3-acetoxy-5a-chloro-6/i-hydroxy-20-oxo-pregnane and 32 grams of iodineare then added and the solution is kept at the boil While beingirradiated with a 1000 Watt lamp and stirred until the color of iodinehas completely disappeared (about 30 to 90 minutes). The whole is thencooled, the undissolved salts are filtered off and the filter residue isrinsed with cyclohexane. The filtrate is washed with dilute sodiumthiosultate solution and with water, dried and evaporated in a water-jetvacuum. Crystallization of the crude product from ether yields 19.2grams of pure 3B-acetoxy-5a-chloro-6;8:l9-oxido-20-oxopregnane meltingat to 153 C. From the mother liquor another 3.3 grams of a slightly lesspure sub stance can be isolated. Optical rotation of the pure compound[ot] =-|65 (in chloroform). Its infra-red spectrum contains bands, interalia, at 5.78, 5.88, 6.70, 8.13, 9.12, 9.66, 10.60, 10.86 and 11.75,.

In an analogous manner there are obtained from 3,8:17a diacetoxy 5achloro-6/3-hydroxy-20-oxopregnane the 35:17 diacetoxy 5a chloro-68:19-oxido 20 oxo pregnane melting at 187 to 187.5 C.,

from 35 acetoxy 50c chloro 65 hydroxy 17 a-valerianloxy-20-oxo-pregnanethe 3,8-acetoxy 5a chloro- 6'fi:19-oxido-l7wvalerianyloxy-20-oxo-pregnane, and

from 36 acetoxy-5ot-chloro-6B-hydroxy-17a-methoxy-20- oxo-pregnane the3B acetoxy-5a-chloro-6p:19-oxido- 17wmethoxy-20-oxo-pregnane.

The chlorohydrin used as starting material is prepared in the followingmanner: A solution of 150 grams of pregnenolone acetate in 5 liters ofether is treated with 150 grams of chlorinated lime (containing 30% ofactive chlorine) and 8.2 liters of water and the reaction mixture isvigorously stirred. After 5 minutes 105 cc. of glacial acetic acid andafter another 25 minutes 500 cc. of potassium iodide solution of 10%strength are added. Finally, the aqeuous phase is separated, and theetheral solution is washed with sodium thiosulfate solution of 10%strength, dilute sodium bicarbonate solution and with water, dried andevaporated in a water-jet vacuum. The residue is treated with 800 cc. ofacetone and kept overnight at C., to yield 47.5 grams, and from themother liquor another 58 grams, of3fl-acetoxy-5a-chloro-6B-hydroxy-20-oxo-pregnane which melts at 196 to197 C. after recrystallization from acetone. Optical rotation [a] =+25(in chloroform). The infra-red spectrum of the compound displays bands,inter alia, at 2.75, 5.78, 5.88, 8.12, 8.68, 9.68 and 9.72 1.

In an analogous manner addition of hypochlorous acid on to thel7-a-acetoxy-pregnenolone acetate yields 351171diacetoxy-Sat-chloro-6fl-hydroxy-20-oxo-pregnane.

(b) 10.0 grams of 3B-flC6tOXY-5a-ChlOIO-6fl:19-0Xid0- 20-oxo-pregnane in180 cc. of acetic anhydride are treated with 4.0 grams ofpara-toluenesulfonic acid and heated in a bath maintained at 140 to 150C. for 4 hours under a pressure of 50 to 60 mm. Hg, during which 90 cc.of solvent are distilled off. The reaction mixture is cooled, pouredover ice and Water and extracted with a 3:1-mixture of ether andmethylene chloride. The extracts are washed with sodium bicarbonatesolution and with water, dried and evaporated. The residue (10.40 grams)is dissolved in benzene and the solution is filtered through 100 gramsof alumina. The eluates yield 10.1 grams of crude product which stillcontains about 15% of starting ma terial. Crystallization from methylenechloride+ether+ petroleum ether yields pure A-3fi:20-diacetoxy-5uchloro-65:l9-oxido-pregnene melting at 171 to 172 C.Optical rotation [a] =+18.4 (in chloroform). The infra-red spectrum ofthe compound contains bands, inter alia, at 5.76, 6.70, 7.30, 8.16,9.13, 10.60 and 10.87

A solution of 10.1 grams of crude A-3;3:20-diacetoxy-a-chloro-6B:19-oxido-pregnene in 250 cc. of benzene istreated with 240 cc. of an ethereal solution of perbenzoic acid(containing 2 molecular equivalents of per-acid calculated on the enolacetate) and kept for 5 hours at room temperature, after which time70.2% of the amount of per-acid calculated for complete oxidation hasbeen consumed. The reaction mixture is diluted with ice Water, extractedwith ether and the extracts are washed with water, sodium bicarbonatesolution and water. The dried ethereal solution yields 9.90 grams ofcrude epoxide. After recrystallization from methylene chloride+etherpure 35:20-diacetoxy 5u-chloro-6p:19;l7a:20-bisoxidopregnane melts at192 to 194 C. Optical rotation [a] =-l-14.4 (in chloroform). Theinfra-red spectrum 4 of the compound contains bands, inter alia, at5.76, 6.70, 7.30, 8.13, 8.58, 9.67, 10.66 and 1 0181;!

A mixture of 10.0 grams of crude 38z20-diacetoxy-5achloro-613:19,17a:20-bisoxido-pregnane, 800 cc. of alcohol and 45 cc. of aqueous sodium hydroxide solution of 2.4% strength iskept for one hour at room temperature, treated with 500 cc. of Water andconcentrated in a waterjet vacuum to half the volume. The concentrate isheated for 3 hours at 60 C., and the precipitate is filtered ofi,thoroughly washed with water and the filter residue is dried, to yield9.85 grams of crude product which after crystallization from methylenechloride-l-methanol yields 3.90 grams of pure3,8:l7ot-dihydroxy-5oc-chloro-6fi:19- oxido-20-oxo-pregnane melting at251 to 253. Optical rotation [u] =-|-22.4 (in chloroform+alcohol). Fromthe mother liquor another compound separates out which melts at 251 to253 0.; it is probably a rearrangement product of the above diol.

A mixture of 200 mg. of 3,8:17a-dihydroxy-5a-chloro-618:19-oxido-20-oxo-pregnane, 1.0 cc. of acetic anhydride and 1.0 cc. ofpyridine is stirred for 14 hours, with the starting material slowlypassing into solution. The solution is then poured into ice water andextracted with a mixture of ether and methylene chloride. The extractsare washed with water, hydrochloric acid, sodium bicarbonate solutionand with water and dried, to yield 210 mg. of crude product which iscrystallized from ether+petroleum ether to yield 185 mg. of pure3fi-acetoxy-5a-chloro- 6B:19-oxido-17a-hydroxy-ZO-oxo-pregnane meltingat 166 to 167 C. Occasionally, the compound is obtained in a crystallinemodification melting up to about 175 C. Optical rotation [a] =2.1 (inchloroform). Its infrared spectrum contains bands, inter alia, at 2.74,2.82, 5.76, 5.85, 6.69, 7.30, 8.10, 9.65 and 10.86;.

A mixture of mg. of 35:l7a-dihydroxy-5a-chloro-6B:19-oxido-20-oxo-pregnane, 1.0 cc. of acetic anhydride and 100 mg. ofpara-toluene sulfonic acid is stirred for 2% hours at 40 C., then pouredinto a mixture of 50 cc. of ice water and 0.5 cc. of pyridine, dilutedwith ether after 10 minutes, and the extracts are washed with sodiumbicarbonate solution and with water. Recrystallization of theevaporation residue (106 mg.) from ether+petroleum ether yields 98 mg.of pure 3p:17u-diacetoxy-5a-chloro- 613:l9-oxido-20-oxo-pregnane meltingat 187 to l87.5 C. Optical rotation [a] =--6.2 (in chloroform). Theinfra-red spectrum of the compound contains bands, inter alia, at 5.77,6.68, 7.79, 8.10, 9.65, 10.39 and 10.85 1.

The identical compound can also be prepared by acetylating 4.0 grams of3fi-acetoxy-5a-chloro-6fl:19- oxido-17a-hydroxy-20-oxo-pregnane for 2%hours at 40 to 50 C. in 40 cc. of acetic anhydride with addition of 4.0grams of para-toluenesulfonic acid. The reaction mixture is cooled,poured into a mixture of 1 liter of ice water and 10 cc. of pyridine,the whole is stirred for 15 minutes and the precipitate is filtered off,Washed with water, taken up in ether, and the solution is washed untilit is neutral, dried and evaporated. The residue (3.85 grams) yields oncrystallization from ether+petroleum ether 3.0 grams of 313:17a-diacetoxy-5a chloro 6,8: 19 oxido-20-oxo-pregnane melting at 187 to187.5 C.

A mixture of 2.8 grams of the latter compound, 100 cc. of methanol and500 mg. of potassium carbonate is stirred in 2.5 cc. of water for 13hours at room temperature, then diluted with water, the methanol isdistilled off in a waterjet vacuum, the residue is extracted with ether,and the extracts are washed with water, dried and evaporated. Theresidue (2.52 grams) yields on crystallization from methylenechloride-l-methanol 1.98 grams of 3,8-hydroxy- 5u-chloro-6,8: 19 oxido17a acetoxy 20-oxo-pregnane melting at 238 to 241 C. After onerecrystallization the melting point rises to 243 to 245 C.

A solution of 425 mg. of this compound in 15 cc. of acetone is treatedat 5- to 6 C. with 0.5 cc. of a solution, diluted with water to 50 cc.of 13.3 grams chromium 7 trioxide in 11.5 cc. of concentrated sulfuricacid. The

5 whole is stirred for 30 minutes at -5 C., and a solution of 5.5 gramsof crystalline sodium acetate in 10 cc. of Water and 35 cc. of benzeneis added. The organic phase is separated, Washed with semi-saturatedsodium chloride solution, dried and evaporated in a water-jet vacuum, toyield 450 mg. of crude 3:20-dioxo-5a-chloro-6/3:19-oxido-17u-acetoxy-pregnane. The pure compound, obtained byrecrystallization from methylene chloride+petroleum ether, melts at 156to 158 C. with decomposition, then solidifies again and melts finally at185 to 190 C. The infra-red spectrum of the compound contains bands,inter alia, at 5.84, 6.75, 6. 82, 7.35, 8.15, 8.30, 9.10, 9.32, 9.70,10.35 and 11.00

A solution of 350 mg. of 3120-diXO-5a-Chl01O-6 3I19-oxido-17ot-acetoxy-pregnane in 100 cc. of methanol is treated with asolution of 600 mg. of potassium acetate in 70 cc. of water and whilestirring about half the solvent is first distilled off and the remainderis evaporated to dryness in a water=jet vacuum. The residue is thendissolved in 70 cc. of water and a mixture of ether+methylene chloride3:1, the organic phase is washed with water, dried and evaporated, toyield 308 mg. of a crude product which on recrystallization fromether+petroleum ether yields in two portions a total of 275 mg. of pureA -3:20-dioxo-6 8:l9-oxido-17a-acetoxy-pregnene melting at 190 to 192 C.Optical rotation [cc] =109 (in chloroform). The infra-red spectrum ofthe compound contains bands, inter alia, at 5.75, 5.82, 5.98, 7.30, 807,8.35, 9.07, 9.75, 10.35, 10.55, 11.37 and 12.30;.

Example 3 5.0 grams of the 18:20-lactone of3fl-acetoxy-5achloro-65:20-dihydrOXy-Su-pregnane-18-acid are reacted in1.5 liters of cyclohexane with lead tetraacetate and iodine as describedin Example 2, part (a). When the crude product obtained as described inthat example is crystallized from benzene, it yields the pure18:20-lactone of 3fi-acetoXy-5u-chloro-6p:19-oxido-20p-hydroxy-5a-pregnane-18-acid melting at 229 to 234 C. Optical rotation [a] =48.3(in chloroform).

When the latter product is hydrolyzed with potassium carbonate inmethanol it yields the 18:20-lactone of 3,8:205 dihydroxy5a-chloro-6p:19-oxido-5a-pregnane- 18-acid which is directly oxidizedwith 'chromic acid+sulfuric acid in acetone at 0 C. to the crude18:20-lactone of 3 0x05a-chloro-6[3:19-oxido-20/3-hydroxy-5a-pregnane-18-acid. From the latterproduct hydrochloric acid is eliminated by boiling for one hour inpyridine, whereupon there is obtained for the 18:20-lactone of A -3-oxo-6p:19-oxido-20-B-hydroxy-pregnene-1S-acid which, after having beenrecrystallized from methylene chloride +ether, melts at 259 to 260 C.Optical rotation [cc] =-111 (in chloroform).

The 5a-chloro-6B-hydroxy compound used as starting material is obtainedas described in Example 2, part (a), by adding hypochlorous acid on tothe 18:20-lactone of A 3,3 acetoxy ZOB-hydroXy-pregnene-1'8-acid; thiscompound is prepared by treating A -3fi-acetoxy-20B-hydroxy-pregnenewith lead tetraacetate and iodine in boiling cyclohexane and subsequentoxidation with chromium trioxide and pyridine with addition of silverchromate at 60 C. After having been recrystallized from methylenechloride+ether the pure 18:20-lactone of 3*fi-acetoxy- 50c chloro 6Bhydroxy-ZO S-hydrOXyJa-pregnane-18- acid melts at 227 to 228 C. Opticalrotation [ed- =-48.3 (in chloroform).

Example 4 3 grams of 3,8acetoxy-5a-chloro-6B-hydroxy-16:17aoxido-ZO-oxo-Sa-pregnane are reactedas described in Example 2, part (a), with lead tetracetate and iodine incyclohexane, to yield 3.5 grams of a crude product which onrecrystallization from methylene chloride+ether yields 3B acetoxy 5achloro 6B:19;16:17-ot-bisoxido-20- oxopregnane melting at 230 to 233 C.Optical rotation [a] =+36.3 (in chloroform).

Hydrolysis of this compound with potassium carbonate in methanol yieldsthe crude 3/8-hydroxy-5a-chlor0- 6,8119;16:17 x bisoxido 20oxo-5a-pregnane (melting at 241 to 247 C.), which upon oxidation withchromium trioxide in pyridine as described in Example 1, affords the A3:20 dioxo-6fi:19;16:17x-bisoxido-pregnene( 6p:l9;16:17a bisoxidoprogesterone) melting at 154 to l56 C.

The Six-chloro compound used as starting material is prepared by addinghypochlorous acid on to the known A 3p acetoxy16:17a-oxido-20-oxo-pregnene as described in Example 2, art (a). Afterrecrystallization from acetone-f-hexane the resulting pure3,6-acetoxy-5achloro 6,8 hydroxy 16:17a-oxido-20-oxo-5a-pregnane meltsat 194 to 198 C. Optical rotation [a] =7.8 (in chloroform).

Example 5 A suspension of 17.5 grams of lead tetracetate and 8.0 gramsof calcium carbonate in 800 cc. of cyclohextime is first heated for 30minutes to boiling point While stirring. 4.0 grams 3B1llocIZOBtriacetoxy5a-chloro 6,8-hydroxy-preg'nane and 5.13 grams of iodine arethen added and the mixture is heated for another hour to boiling pointwhile being stirred and exposed to a 500- watt lamp, the color of theiodine slowly disappearing. After the reaction time has expired, themixture is cooled, the insoluble salts are separated by filtration andthe filtrate is washed with 10% sodium thiosulfate solution and withwater. The aqueous solutions are extracted once more with ether and thecombined organic solutions are dried and evaporated in a Water-jetvacuum. The partly crystallizing crude product obtained (6.146 grams) isdissolved in 100 cc. of glacial acetic acid to reduce the startingmaterial contained therein and the solution is stirred for 2 hours at C.after adding 10 grams of zinc dust. The undissolved zinc is thenfiltered off and the filtrate is diluted with methylene chloride andwashed with sodium bicarbonate solution and with water. 4.253 grams ofcrude product are obtained from the dried organic solutions afterevaporation. By crystallization from ether, 923 mg. of3B1110L;20,6-tIlaCetOXy-50L-Ch1OIO-6BI19- oxidopregnane having a meltingpoint of 228230 C. can be separated therefrom (conversion from 185 C.;[a] =6.Z (in chloroform); IR bands inter alia at 5.77 and 8.09,(acetates), 9.63 9.75 and 1084 The mother liquor is evaporated todryness and chromatogr-aphed on grams of aluminum oxide. With 900 cc. ofhexane, 900 cc. of hexane-benzene mixture (4:1) only 81 mg. of oilyby-products are eluted. From the fractions eluted with another 300 cc.of benzene-hexane mixture (2: 1) there are obtained by crystallizationfrom aqueous methanol 119 mg. of A -3fl:11a20fi-triacetoxypregnene,which has been produced by zinc reduction of theSac-ChlOIO-6/3-l1Yd1'OXY compound. The following 300 cc. ofbenzene-hexane mixture (2:1) and 300 cc. of benzene contain mixtures ofsubstances, while the evaporation residues of the fractions eluted with900 cc. of benzene and 600 cc. of benzene-ethyl acetate mixture (9:1),when crystallized from ether, yield a further 411 mg. of theabove-described 3,8311a220/3 triacetoxy-Sa-chloro-Gfl:19-oxido-pregnane. Finally from the fractions eluted with benzene-ethylacetate mixture (1:1), with ethyl acetate and with methanol 718 mg. of3/3:11a:20,B-triacetoxy-5u-' chloro-6 3:19-oxido-19-hydroxypregnanehaving a melting point of 232233 C. are obtained by crystallization frommethylene chloride-ether; [oc] =-13.2 (in chloroform-alcohol in a ratio1:1). IR bands inter alia at 2.7911. and 293 (0H), 5.78 2 and 8.12(acetates); 9.30 9.70,, 10.55 and 10.91

The 3pzllaz20p triacetoxy-Sa-chloro-6B-hydroxypregnane employed asstarting material is prepared as follows: 18.71 grams of A-3-ox0-11u-acetoxy-2Op-hydroxypregnene are heated to boiling point in100 cc. of isopropenyl acetate after adding 0.1 cc. of concentratedsulfuric acid. After one hour, 10 cc. of solvent are distilled 01f,boiling is then continued for another hour under reflux and the solutionis then evaporated in a water-jet vacuum after adding 500 mg. ofanhydrous sodium acetate. The residue is taken up in methylene chlorideand the solution is Washed with water, dried and once more evaporated.From the crude product (21 grams), 13.66 grams of pure A8:11a:2Ofi-triacetoxy-pregnatriene having a melting point of 145-150 C.are obtained by crystallization from ether; [a] =-144.3 (in chloroform);UV maximum at 235 m (e=195()0); IR bands inter alia at 5.77 (withshoulder at 5.68 and 8.16,u (acetates), 9.76;;; 10.40;; and 10.83

12.0 grams of this enol acetate are dissolved in 900 cc. of alcohol. Asolution of 6.0 grams of sodium borohydride in 120 cc. of 70% aqueousalcohol is added to the solution, which has been cooled to +5 C., andthe reaction mixture is allowed to stand for 3 days at C. 10 cc. ofglacial acetic acid are then dropped in while stirring and the reactionmixture is concentrated in a water-jet vacuum to about 100 cc., dilutedwith methylene chloride and washed with water. 11.52 grams of a residueare obtained from the dried methylene chloride solution afterevaporation and from this 9.78 grams of pure A -3;3-hydroxy-1laz20fl-diacetoxypregnene can be isolated by crystallization fromether. The compound, after being dissolved once more in methanol andallowed to crystallize, melts at 162- 165 C. [a] =-69.6 (in chloroform);IR bands inter alia at 2.74;/. (OH), 5.78;]. and 8.09;; (acetates);9.76; and 10.45

9.78 grams of this compound are allowed to stand overnight at roomtemperature in 50 cc. of pyridine and 30 cc. of acetic anhydride. Thereaction mixture is then evaporated to dryness in a water-jet vacuum andthe residue is crystallized from aqueous methanol. 10.1 grams of A35:11a:ZOB-triacetoxypregnene having a melting point of 141-143" C. areobtained; [a] =59.4 (in chloroform). IR bands inter alia at 5.78;; and8.09;; (acetates), 9.76 10.44;; and 10.93;/..

3.0 grams of A -3;3:11a:ZOB-triacetOXypIegnene are dissolved in 180 cc.of ether. After adding 180 cc. of water and 3.0 grams of chlorinatedlime, the reaction solution is thoroughly stirred and 2.1 cc. of glacialacetic acid are then added. The two phases are then well mixed for 40minutes with vibromixer, 50 cc. of 2% sodium thiosulfate solution and 50cc. of 5% potassium iodide solution are then added, separation iscarried out and the organic solution is washed several times with water.1.78 grams of 3,8:1la120,8 triacetoxy 5a-chloro-6B-hydroxypregnanehaving a melting point of 225-227 C. are obtained from the evaporationresidue (3.417 grams) by crystallization from ether; [a] =-43.2 (inchloroform); IR bands inter alia at 2.74;]. (OH); 5.78;; and 8.09;;(acetates); 9.30;t; 9.56;;; 9.75;; and 10.45

Example 6 250 mg. of31-3:11o;:20B-triacetoxy-5a-chloro-65:19-oxidopregnane are dissolved in50 cc. of methanol and the solution is boiled under reflux for 10 hoursafter adding 500 mg. of potassium carbonate and 12.5 cc. of water. 1.0cc. of glacial acetic acid is then added, the mixture is evaporated toabout cc. in a water-jet vacuum and diluted with methylene chloride andwater, separation is carried out and washing to neutrality with dilutesodium bicarbonate solution, and the organic solution is dried andevaporated. 160 mg. of crystallized3B:11o:20;3-trihydroxy-5u-chloro-6fi:19-oxidopregnane, which isprecipitated from methanol-ether in methanol-containing crystals havinga melting point of 264266 C., are obtained; [u] =-25.9 (in chloroform):IR bands inter alia at 3.03 (OH), 9.15 9.63;1.; 9.80;; and another 10bands .between 10.24;; and 12.60;/. (in Nujol).

295 mg. of crude 3B:1la:ZOB-trihydroxy-5a-chloro- 65:19-0xidopregnaneare dissolved in cc. of acetone and stirred at 0 C. for 15 minutes afteradding 1.0 cc. of a 26.6% solution of chromium trioxide in sulfuric acidof 42% strength. 3.0 cc. of isopropanol are then added, stirring iscontinued for another 5 minutes at 0 C., a solution of 2.0 grams ofcrystalline sodium acetate in 10 cc. of water is added and the reactionmixture is concentrated to about 30 cc. in a water-jet vacuum anddiluted with methylene chloride and the organic solution is washed withwater, dried and evaporated (residue: 288 mg). The 3:11:20trioxo-5a-chloro-6fl:19-oxidopregnane obtained in this way melts, afterbeing dissolved in methylene chloride-ether and allowed to crystallize,within a few degrees between and C. with decomposition, according to therate of heating; [a] =+167 (in chloroform); IR bands inter alia at 5.84;(with shoulder at 5.80;i); 6.681.147.3811;8.55/L;9.12/L;9-68LL and10.56;1..

200 mg. of crude 3: 11:20-trioxo-5ot-chloro-6B: 19-oxidopregnane aresuspended in 30 cc. of methanol and the mixture is stirred for 30minutes at 60 C. after adding 400 mg. of crystalline sodium acetate and1.5 cc. of water. The solution is then concentrated and diluted withmethylene chloride and the extract is washed with water, dried andevaporated. mg. of crystallized A -3:11:20-trioxo- 65:19-oxidopregnene,which melts at 265268 C. after dissolution in methylene chloride-etherand crystallization, are obtained. [a] =-13.4 (in chloroform); UVmaximum at 236 m;; (c=11800); IR bands inter alia at 5.84;; (11- and20-ketone); 5.95 (3-ketone), 6.72;; 8.33% 8.61 9.75;i and 11.41/L.

Example 7 500 mg. of3,6:11m:ZOB-triacetoxy-Sa-chloro-6;3:19-oxidopregnane are dissolved in100 cc. of methanol and allowed to stand for 18 hours at 25 C. afteradding a solution of 1.0 gram of potassium carbonate in 25 cc. of water.2 cc. of glacial acetic acid are then added, the reaction mixture isconcentrated to about 20 cc. in a water-jet vacuum and diluted withmethylene chloride and the organic solution is washed with water, sodiumbicarbonate solution and water. From the residue of the dried methylenechloride solution there are obtained by crystallization from aqueousmethanol 110 mg. of 3fi-hydroxy-5a-chloro-6B:19-oxido-1laz20fl-diacetoxypregnane in hydrous crystals which lose waterof crystallization at 114-116 C, and melt at 168170 C.; [u] =20.2 (inchloroform); IR bands inter alia at 2.78;; (OH); 5.77;; and 8.11;/.(acetates); 9.52;;; 9.78;; and 10.93;/..

The mother liquor which, in addition to further amounts of the abovecompound, also contains 35:20pdihYdIOXY-Sot-ChlOIO-Gfii19-oxido-1lu-acetoxypregnane, is evaporated to dryness and the residue(340 mg.) is dissolved in 30 cc. of acetone. 1.0 cc. of a 26.6% solutionof chromium trioxide in sulfuric acid of 42% strength is added to thesolution, which has been cooled to 0 C., and stirring is carried out for15 minutes at 0 C. 3.0 cc. of isopropanol are then added, dilution withmethylene chloride is carried out after another 5 minutes and thesolution is washed several times with water. The dried methylenechloride solution is evaporated to dryness and the residue (312 mg.),which contains 3-oxo-5a-chloro-6B:19-oxido- 11a:20,8 diacetoxypregnaneand 3 :20 dioxo Sat-chloro- 6B:19-oxido-1lot-acetoxypregnane, isdissolved in 30 cc. of methanol and heated for one hour to 60 C. afteradding a solution of 500 mg. of crystalline sodium acetate in 6 cc. ofwater. The mixture is then concentrated in a water-jet vacuum, dilutedwith methylene chloride and washed several times with water. 286 mg. ofcrude product are obtained from the dried methylene chloride solu tionafter evaporation. By repeated crystallization from ether-methylenechloride, 26 mg. of pure A -3-oxo-6 8rl9- oxido-lImZOB-diacetoxypregnenehaving a melting point of 274-280 C. can be isolated therefrom. UVmaximum 8 at 235 my (E=12600); IR bands inter alia at 5.78,LL and 8.11(acetates); 5.96, (3-ket0ne); 6.74 9.26 9.75 10.43,u and 11.40,u..

The mother liquor is evaporated to dryness and the residue, dissolved inbenzene, is chromatographed on 10 grams of aluminum oxide. From thefraction eluted with benzene A 3:20- dioxo 6,8219 oxido 11oz-acetoxypregnene having a melting point of 187189 C. can be isolated bycrystallization from ether-methylene chloride; [a] =+86.6 (inchloroform); UV maximum at 237 mu (e=11500); 5.95 (3-ketone); 6.27;.t;7.27 1; 8.09,u.; 9.28m 9.75,u; 10.35 10.62 10.85 and 11.40

Further amounts of the above-described 11a:20/3-diacetate areprecipitated from the mother liquor of the same fraction on standing fora long time.

Example 8 A solution of 1.48 grams of crude3flzllaz20fl-trihydroxy-5a-chlor-o-6fi:19-oxidopregnane in 430 cc. ofacetone is cooled to 5 C., mixed with 4.3 cc. of a 26.6% solution ofchromium trioxide in sulfuric acid of 42% strength, and the whole isstirred for 1 hour at to C. 13 cc. of isopropanol are then dropped inand then a solution of 4.3 grams of potassium acetate in 45 cc. ofWater, the whole is concentrated in a water-jet vacuum to about 35 cc.and repeatedly extracted with methylene chloride. The extracts arewashed with water and dried, to yield 1.352 grams of crude3:11:20-trioxo-5a-ch1oro-6/8:19- oxidopregnane which is dissolved in 50cc. of pyridine, and the solution is heated for 1 hour at 100 C., thenconcentrated in a water-jet vacuum to about cc. and extracted withmethylene chloride. The extracts are washed with N-hydrochloric acid andWith water, dried and evaporated. The residue (1.351 grams) yields oncrystallization from methylene chloride+ether 795 mg. of A -3:11:20-trioxo-6fi:19-oxidopregnene melting at 190-191 C. Optical rotation[a] =+134 (in chloroform). Ultraviolet maximum at 236 m (e=11750).Infra-red bands inter alia at 5.83, 5.94, 6.70, 7.33, 8.30, 8.62, 9.68,9.78 and 11.40

10 What is claimed is: 1. A -3-oxo-65:19-oxido-pregnenes of the formulawherein R stands for a member selected from the group consisting ofhydrogen, oxo, hydrogen together with hydroXy and hydrogen together withacyloxy, R stands for a member selected from the group consisting ofhydrogen, hydroxy, acyloxy and a l6217ot-0Xid0 group, R stands for amember selected from the group consisting of 0x0, hydrogen together withhydroxy and hydrogen together with acyloxy.

. A -3 :20-dioxo-6B: 19-oxid0-pregnene.

A -3 :20-dioxo-6B: 19-oxido-17a-hydroxy-pregnene. A -3 :20-dioxo-6,8:19-oxido-17u-acetoxy-pregnene.

. A -3 :20-dioxo-6fl: 19;16: 17u-bisoxido-pregnene.

. A -3-oxo-6fi: 19-oxido-1 10 ZOB-diacetoxy-pregnene. A -3 :20-dioxo-6B:19-oxido-1lot-acetoxy-pregnene.

. 13 -3: 1 1 :20-trioxo-6{3: 19-oxido-pregnene.

A 3 :20 dioxo-6B:19-oXido-17a-capronyloxy-pregw es nene.

References Cited UNITED STATES PATENTS 2,837,464 6/1958 Nobile 195-513,001,989 9/1961 Ringold et a1. 260239.55 3,008,957 11/1961 Ringold etal. 260-23955 OTHER REFERENCES Holysz, J. Am. Chem. Soc., vol. (1953),page 4432.

ELBERT L. ROBERTS, Primary Examiner.

LEWIS GOTTS, Examiner.

Cont

, 22 3? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,3 4-6,569 Dated October 1Q, 1967 In nt 1-( Albert Wettstein et a1 Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 10, in the formula of claim 1 CH (3H C=R should be (1:11 +..R...R

SIGNED AND SEALED MAR 3 1970 llwnllmqh.

mil-Ill I. swam. Ill Amlfloffim Oo-unom ot hm!

1. $4-3-OXO-6B:19-OXIDO-PREGNENES OF THE FORMULA